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British Journal of Oral and Maxillofacial Surgery 47 (2009) 294–297

Available online at www.sciencedirect.com

isphosphonate osteonecrosis: a protocol for surgicalanagement

eorge Markose ∗, Fiona R. Mackenzie 1, W.J.R. Currie 2, W.S. Hislop 3

ept. of Oral & Maxillofacial Surgery, Crosshouse Hospital, Kilmarnock, Ayrshire KA2 0BE, UK

ccepted 9 January 2009vailable online 23 February 2009

bstract

e present a protocol for the management of a subgroup of patients with bisphosphonate osteonecrosis who presented with painful, exposed,

ecrotic, alveolar bone. It is simple and can easily be adapted to suit anatomical variations of the oral cavity. Current guidelines based ononsensus for the management of bisphosphonate-induced osteonecrosis fail to provide mucosal coverage, which is a primary requirement inanaging the condition. We have evaluated the results of a group of 15 patients and analysed their postoperative progress for 24 months.2009 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

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eywords: Bisphosphonate; Osteonecrosis; Surgical management

ntroduction

isphosphonate osteonecrosis of the jaw is a growing prob-em with no widely accepted protocol for treatment. It isefined as the presence of exposed necrotic alveolar bonehat does not resolve over a period of 8 weeks in a patientaking bisphosphonates who has not had radiotherapy tohe jaw.1 Osteonecrosis of the jaw may remain asymp-omatic for a long time in the absence of infection. Signs andymptoms that may present before the development of clini-ally detectable osteonecrosis include pain, mobility of teeth,ucosal swelling, erythema, and ulceration. The lesions may

ccur spontaneously or at the site of a dentoalveolar proce-

ure. Radiographs may not show appreciable changes in thearly stages of osteonecrosis but, when there is extensive bony

∗ Corresponding author. Tel.: +44 1563 577296; fax: +44 1563 577300.E-mail addresses: gmarkose@gmail.com (G. Markose),

ona.mackenzie@aaaht.scot.nhs.uk (F.R. Mackenzie),oger.currie@aaaht.scot.nhs.uk (W.J.R. Currie),tuart.hislop@aaaht.scot.nhs.uk (W.S. Hislop).

1 Tel.: +44 1563 577296; fax: +44 1563 577300.2 Tel.: +44 1563 577293; fax: +44 1563 577300.3 Tel.: +44 1563 577288; fax: +44 1563 577300.

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266-4356/$ – see front matter © 2009 The British Association of Oral and Maxillofaciadoi:10.1016/j.bjoms.2009.01.007

nvolvement, regions of mottled bone can be seen similar tohose seen in diffuse osteomyelitis.

Bisphosphonates have been in use for over two decades,nd during this time, the number available has expanded, withhe newest compounds up to 3 times more potent than theirredecessors. Bisphosphonates bind avidly to apatite crystalsf bone and inhibit their growth; they inhibit osteoclasts usingeveral disruptive effects on their cytoskeleton and oxidativeathways.2–4 As they are not metabolised they have a longuration of action, which may last up to 10 years.

Bisphosphonates are also thought to have a complex inter-ction with growth hormone and insulin-like growth factor-Io reduce blood circulation in bones.5,6 They also inhibitndothelial cell function, decrease proliferation, increase theate of apoptosis, and reduce capillary-tube formation.7 Thentiangiogenic properties of bisphosphonates are reflected inheir ability to reduce circulating levels of the potent angio-enic factor vascular endothelial growth factor (VEGF), asan be seen in patients with breast cancer who have bonyetastases.1,8

Though bisphosphonates are given orally in the manage-ent of osteoporosis, they are given intravenously to patientsith metastatic breast cancer, multiple myeloma, hypocal-

aemia of malignancy, and Paget disease of bone. Since 2003,

l Surgeons. Published by Elsevier Ltd. All rights reserved.

l and Maxillofacial Surgery 47 (2009) 294–297 295

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Fig. 2. Teeth associated with osteonecrotic bone extracted atraumaticallyunder antibiotic cover.

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G. Markose et al. / British Journal of Ora

hen the first report9 that drew attention to bisphosphonatesteonecrosis was published, many patients have been diag-osed with the condition. Bisphosphonate osteonecrosis hasncreased in incidence in recent years probably because ofhe increased use of the more potent bisphosphonates thatre given intravenously. However, reports have suggested thatisphosphonates given orally over long periods may also bessociated with bisphosphonate osteonecrosis.1

The consensus view stated in the position paper by themerican Association of Oral and Maxillofacial Surgeons,1

ecommended a conservative approach, with only superficialebridement to relieve sharp points.

Our experience with a group of patients who presentedith osteonecrosis associated with pain and infection, haseen that aggressive elimination of necrotic alveolar bone,hich permits primary mucosal closure without the need

or extensive mobilisation of mucosa, can provide quick andeliable results.

atients and methods

he criteria for selection included consecutive patients withisphosphonate osteonecrosis associated with pain and infec-ion limited to the small areas of alveolar bone (Fig. 1).atients whose bisphosphonate osteonecrosis was asymp-

omatic or who presented with pathological fractures orxtraoral fistulas were excluded.

All the operations took place in the same unit and followedhe same protocol. All patients were give one preoperativeose of clindamycin. The involved teeth were extracted underocal anaesthesia (Fig. 2). The surrounding exposed necroticlveolar bone was removed to a level where bleeding compactone was covered by periosteum, and until there was adequateucosa to allow primary closure. (Fig. 3) The wound was

losed with resorbable sutures (Fig. 4). Patients were advisedo maintain good oral hygiene with regular tooth-brushingnd 0.2% chlorhexidine mouthwash.

ig. 1. Osteonecrosis caused by bisphosphonates and associated with painnd infection.

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ig. 3. Aggressive removal of necrotic alveolar bone permits closure witho need for extensive mobilisation of the mucosa.

Patients were reviewed weekly postoperatively. They werexamined for the presence of mucosal closure (Fig. 5), wound

ehiscence, pain, discomfort, and oral hygiene. Review con-inued until the mucosa had closed completely. They werehen reviewed at 3, 6, 12, and 24 months.

Fig. 4. After irrigation the wound is closed with resorbable sutures.

296 G. Markose et al. / British Journal of Oral and M

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Fig. 5. Complete mucosal closure.

esults

e studied 15 patients who presented with bisphosphonatesteonecrosis; there were 9 men and 6 women, mean age4 years (range 49–78). Eleven of these had presented afterultiple tooth extractions, and 4 with spontaneous exposure

f alveolar bone. Eight patients were taking pamidronatentravenously, and 7 zolendranate (Table 1).

Postoperatively, 14 patients had complete closure of theucosa at the 2-week review, and in one it was completely

losed by 3 weeks postoperatively. None of the patients com-lained of pain or discomfort after their wounds had settledown. All patients are still being followed up, and have soar been free of symptoms.

able 1etails of patients studied.

ean age (years) 64ange 49–78ex (M/F) 6:9

iagnosisBreast cancer 6Multiple myeloma 5Osteoporosis 1Multiple myeloma and osteoporosis 1Prostatic cancer 2

ite of osteonecrosisMaxilla 5Mandible 9Both 1

resentationExposure of bone after extraction 10Spontaneous exposure 5

isphosphonateZolendronate 5Pamidronate 8Both 2

ean (range) duration of treatment (months) 28 (11–56)

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axillofacial Surgery 47 (2009) 294–297

iscussion

ompared with other bones, the jaws have a higher con-entration of bisphosphonates and are therefore at greaterisk of osteonecrosis,10 because bisphosphonates are pref-rentially deposited in areas of good blood supply andigh bone turnover. Patients being given bisphospho-ates intravenously are at least 7 times more likely toevelop bisphosphonate osteonecrosis after dentoalveolarperations.1

In bisphosphonate-induced osteonecrosis, there is no bor-er of “normal” bone, as the entire skeleton is being treatedith the drug. Extensive operations are counterproductive,

nd lead to further exposure of bone and a greater risk ofathological fractures.9 The thin mucosa does not protecthe bone adequately, and these patients respond poorly tostablished treatments for osteomyelitis or osteoradionecro-is. Hyperbaric oxygen has not been effective in limitinghe process.11 Agrillo et al.12 reported that dental extrac-ions are possible without complications in patients withisphosphonate osteonecrosis after treatment with ozone.atients had one cycle before extraction and one cyclefterwards. Each cycle comprised eight, 3-min sessions.zone is thought to help to preserve endogenous antioxidant

ystems and increase fibroblastic and angiogenic activ-ty.

Discontinuation of bisphosphonates offers no short-termenefit. However, if systemic conditions permit, long-termiscontinuation may help in the gradual improvement of clin-cal disease.

Longobardi et al.13 and Magopoulos et al.14 have sug-ested debridement of varying amounts of necrotic bone untilhe surgical margins of bone are bleeding and viable. Theyid not, however, attempt to close the wound primarily.

Although the bone is avascular and necrotic, the overlyingucosa is vascular, and complete mucosal closure will help

t to heal. If debridement of bone is only superficial, exten-ive mobilisation of the mucoperiosteum will be requiredo provide mucosal coverage. Aggressive removal of alve-lar bone, however, would permit mucosal closure withouthe need for such extensive mobilisation. Reduction of themount of periosteal stripping, limits ischaemic damage toarger areas of alveolar bone, the vascularity of which isompromised.

eferences

1. American Association of Oral and Maxillofacial Surgeons positionpaper on bisphosphonate-related osteonecrosis of the jaws. J Oral Max-illofac Surg 2007;65:369–76.

2. Hughes DE, MacDonald BR, Russell RG, Gowen M. Inhibition of

osteoclast-like cell formation by bisphosphonates in long-term culturesof human bone marrow. J Clin Invest 1989;83:1930–5.

3. Hughes DE, Wright KR, Uy HL, Sasaki A, Roneda T, Roodman GD,et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitroand in vivo. J Bone Miner Res 1995;10:1478–87.

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4. Murakami H, Takahashi N, Sasaki T, Udagawa N, Tanaka S, NakamuraI, et al. A possible mechanism of the specific action of bisphosphonateson osteoclasts: tiludronate preferentially affects polarized osteoclastshaving ruffled borders. Bone 1995;17:137–44.

5. Kapitola J, Zak J, Lacinova Z, Justova V. Effect of growth hormone andpamidronate on bone blood flow, bone mineral and IGF-I levels in therat. Physiol Res 2000;49(Suppl. 1):s101–6.

6. Kapitola J, Zak J. Effect of pamidronate on bone blood flow in oophorec-tomized rats. Physiol Res 1998;47:237–40.

7. Fournier P, Boissier S, Filleur S, Guglielmi J, Cabon F, Colombel M,et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats.Cancer Res 2002;62:6538–44.

8. Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM, et

al. Novel antiangiogenic effects of the bisphosphonate compound zole-dronic acid. J Pharmacol Exp Ther 2002;302:1055–61.

9. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avas-cular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg2003;61:1115–7.

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1. Freiberger J, Padilla-Burgos R, Chhoeu AH, Kraft KH, Boneta O,Moon RE, et al. Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series. J Oral Maxillofac Surg2007;65:1321–7.

2. Agrillo A, Petrucci MT, Tedaldi M, Murtazza MC, Marino SM, GallucciC, et al. New therapeutic protocol in the treatment of avascular necrosisof the jaws. J Craniofac Surg 2006;17:1080–3.

3. LongobardiG, Boniello R, Gasparini G, Pagano I, Pelo S. Sur-gical therapy for osteonecrotic lesions of the jaws in patientsin therapy with bisphosphonates. J Craniofac Surg 2007;18:

1012–7.

4. Magopoulos C, Karakinaris G, Telioudis Z, Vahtsevanos K, Dimi-trakopoulos I, Antoniadis K, et al. Osteonecrosis of the jaws due tobisphosphonate use. A review of 60 cases and treatment proposals. AmJ Otolaryngol 2007;28:158–63.